[The long way of angiotensin-converting enzyme inhibitors in the fight against cardiovascular diseases].
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Aged↗
Biomedical subjects
Roberto Ferrari
Publications and source records attributed to Roberto Ferrari.
[Efficacy of angiotensin-converting enzyme inhibitors in secondary prevention].
This paper reports the rationale for the cardiovascular protective effects of angiotensin-converting enzyme (ACE) inhibitors and reviews the overall results of recent randomized clinical trials. ACE-inhibitors prevent degradation of bradykinin, exert anti-ischemic action, inhibit thrombosis and platelet aggregation, are antiatherogenic, improve endothelial function and vessel remodeling, and have anti-inflammatory properties. Previous trials have shown that ACE-inhibitors reduce cardiovascular events in patients with heart failure or ventricular dysfunction. These findings have recently been extended to patients with lower risk profile, no evidence of heart failure and in secondary prevention using lipophilic ACE-inhibitors with high affinity for tissue ACE, i.e. those most likely to have high antiatherosclerotic efficacy. The central role of long-acting lipophilic ACE-inhibitors for cardiovascular protection has been clearly established and they should now be considered as a routine treatment for secondary prevention in the same way as aspirin, beta-blockers and statins.
Angiotensin-Converting Enzyme Inhibitors↗
[Rationale, characteristics and study design of PREAMI (Perindopril and Remodelling in the Elderly with Acute Myocardial Infraction)].
Angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity in patients with heart failure and/or left ventricular systolic dysfunction and in patients with acute myocardial infarction (AMI), especially those with heart failure and/or evidence of left ventricular systolic dysfunction. ACE-inhibitors prevent cardiac events in patients at high cardiovascular risk and/or with documented coronary artery disease. There is a lack of data on the role of ACE-inhibitors in the elderly population with AMI and preserved left ventricular function. Nevertheless, the issue is of primary importance, considering the median age of patients with AMI and heart failure, the high risk of death, heart failure and left ventricular remodeling in the elderly, and the progressive aging of the general population. The multicenter and international (109 centers from five European countries), double-blind, randomized, parallel PREAMI (Perindopril and Remodelling in the Elderly with Acute Myocardial Infarction) trial evaluated the effects of the ACE-inhibitor perindopril in the elderly (aged > or =65 years) with AMI and preserved or mildly depressed left ventricular systolic function (ejection fraction > 40%). The combined primary endpoint was death, hospitalization for heart failure, and left ventricular remodeling (considered as an increase in left ventricular end-diastolic volume > or = 8%). Secondary endpoints included: each single primary endpoint, cardiovascular death, hospitalization for reinfarction or angina, and revascularization. The study involved 1252 patients, with an average age of 73 years, and AMI, treated with recommended usual therapy (antithrombotic drugs, beta-blockers, ACE-inhibitors). After 11 +/- 4 days from AMI, patients were randomized to receive either perindopril (4 mg/day for the first month and 8 mg/day for the remaining 11 months) or placebo, in addition to the recommended conventional therapy. Clinical assessment was performed at fixed times and included two-dimensional echocardiography (to evaluate left ventricular remodeling), Holter electrocardiographic monitoring (to assess heart rate variability and arrhythmias), and blood sampling (for safety evaluation). This review provides details on the background, rationale and study design of PREAMI.
Age Factors↗
[Angiotensin-converting enzyme inhibitors in patients with preserved left ventricular function: from EUROPA to PREAMI].
The trials with angiotensin-converting enzyme (ACE) inhibitors have followed a particular trend: in the first studies treatment was provided to severely ill patients several time (months or year) after the acute event. Thereafter, in few studies ACE-inhibitors were provided within 2 weeks of the event to patients with left ventricular dysfunction after acute myocardial infarction (AMI). In other megatrials ACE-inhibitors were started in unselected patients 24 hours after AMI. Thus, the trend is to provide treatment as early as possible to less selected patients. Recently, ACE-inhibitors have been successfully tested not only to treat the consequences of an infarct, but also to prevent its occurrence. EUROPA is the trial that demonstrated that perindopril (8 mg/day) is indicated in all coronary artery disease patients to reduce cardiovascular mortality and occurrence of AMI. The Perindopril and Remodelling in the Elderly with Acute Myocardial Infarction (PREAMI) is another trial recently terminated in elderly post-AMI patients with preserved left ventricular function. Although not associated with better clinical outcomes (most likely because of the rather short treatment period, 1 year), perindopril significantly reduced the combined primary endpoint (death, hospitalization for heart failure and remodeling) and prevented the progressive left ventricular remodeling occurring in elderly patients even in the presence of small infarct size.
Age Factors↗
[Markers of coronary damage. From diagnosis to prognosis].
UNLABELLED: Cardiovascular disease is a major public health problem. Rapid and accurate diagnosis in the emergency department is essential for timely initiation of treatment, thus any means for improving the speed and accuracy of acute coronary syndrome (ACS) diagnosis can contribute to better clinical and economic outcomes. Measurement of circulating level of troponin has proven to be a sensitive and specific test for cardiac damage detection but they do not discriminate between ischemic and not ischemic etiologies of myocardial injury. Combining troponin with other cardiac biomarkers may offer complimentary information on the underlying pathobiology and prognosis in an individual patient, may increase the analytic sensitivity for myocardial damage and offer insights into the timing and mechanism of myocardial injury. Several prospective epidemiological studies have documented an association between inflammatory markers and cardiovascular disease and their role in primary and secondary prevention and as predictor of mortality. OBJECTIVE: We sought to report a selected but representative evidence on some new biological markers of cardiac damage, including inflammatory cytokines in patients with cardiovascular disease. DATA SOURCES: We searched in Medline from January 1998 to March 2005 for all studies focusing on the diagnostic and prognostic value of new markers of cardiac damage in patients with ACS and heart failure. CONCLUSION: The use of necrotic markers to risk stratify patients with chest pain has become an established practice in the clinical setting while the role of other inflammatory biomarkers, despite being still undefined, seems promising under both pathophysiologic and prognostic perspective.
Biomarkers↗
Distinct roles of transcription factors TFIIIB and TFIIIC in RNA polymerase III transcription reinitiation.
Eukaryotic RNA polymerase (Pol) III is recruited to target promoters by a stable preinitiation complex containing transcription factors TFIIIC and TFIIIB. After the first transcription cycle, reinitiation proceeds through facilitated recycling, a process by which the terminating Pol III rapidly reloads onto the same transcription unit. Here, we show that Pol III is repeatedly recaptured in vitro by the first transcribed gene, even in the presence of a juxtaposed competitor promoter complex, thus suggesting that facilitated recycling is not merely due to a stochastic reassociation process favored by the small size of class III genes. The transcription factor requirements for facilitated reinitiation were investigated by taking advantage of Pol III templates that support both TFIIIC-dependent and TFIIIC-independent transcription. A TFIIIC-less transcription system, in which TFIIIB was reconstituted from recombinant TATA box-binding protein and Brf1 proteins and a crude fraction containing the Bdp1 component, was sufficient to direct efficient Pol III recycling on short ( approximately 100 bp) class III genes. Unexpectedly, however, on longer (>300 bp) transcription units, reinitiation in the presence of TFIIIB alone was compromised, and TFIIIC was further required to reestablish a high reinitiation rate. Transcription reinitiation was also severely impaired when recombinant Bdp1 protein replaced the corresponding crude fraction in reconstituted TFIIIB. The data reveal an unexpected complexity in the Pol III reinitiation mechanism and suggest the existence of a handing-back network between Pol III, TFIIIC, and TFIIIB on actively transcribed class III genes.
DNA-(Apurinic or Apyrimidinic Site) Lyase↗
CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure.
BACKGROUND: Peripheral blood CD34(+) cells and circulating endothelial progenitor cells (EPCs) increase in myocardial infarction and vascular injuries as a reflection of endothelial damage. Despite the occurrence of endothelial dysfunction in heart failure (HF), no data are available on EPC mobilization in this setting. We investigated the pattern of CD34(+) cells and EPC mobilization during HF and their correlation with the severity and origin of the disease. METHODS AND RESULTS: Peripheral blood CD34(+) cells (n=91) and EPCs (n=41), assessed both as CD34(+) cells coexpressing AC133 and vascular endothelial growth factor (VEGF) receptor-2 and as endothelial colony-forming units, were studied in HF patients (mean age 67+/-11 years) and 45 gender- and age-matched controls. Tumor necrosis factor-alpha (TNF-alpha) and its receptors (sTNFR-1 and sTNFR-2), VEGF, stromal derived factor-1 (SDF-1), granulocyte-colony stimulating factor (G-CSF), and B-type natriuretic peptide were also measured. CD34(+) cells, EPCs, TNF-alpha and receptors, VEGF, SDF-1, and B-type natriuretic peptide were increased in HF. CD34(+) cells and EPCs were inversely related to functional class and to TNF-alpha, being decreased in New York Heart Association class IV compared with class I and II and controls. No role was found for the origin of the disease. CONCLUSIONS: CD34(+) cells and EPC mobilization occurs in HF and shows a biphasic response, with elevation and depression in the early and advanced phases, respectively. This could be related to the myelosuppressive role of TNF-alpha.
Adult↗
The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE Trial.
OBJECTIVES: We sought to determine the safety and efficacy of high-dose bolus (HDB) tirofiban in high-risk patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The use of HDB tirofiban in the catheterization laboratory is controversial. In particular, in patients with acute coronary syndromes undergoing PCI, there is no evidence that tirofiban administered in the catheterization laboratory is superior to heparin alone. This finding probably reflects the suboptimal platelet inhibition when tirofiban is employed at RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) regimen. METHODS: A total of 202 patients (mean age 69 +/- 8 years; 137 males [68%]) undergoing high-risk PCI, pretreated with thienopyridines, were consecutively randomized to HDB tirofiban (25 microg/kg/3 min, and infusion of 0.15 microg/kg/min for 24 to 48 h) or placebo immediately before the procedure and then followed for a median time of 185 days (range 45 to 324 days) for the occurrence of the primary composite end point of death, myocardial infarction, target vessel revascularization (TVR), and bailout use of glycoprotein (GP) IIb/IIIa inhibitors. RESULTS: The cumulative incidence of the primary end point was 35% and 20% in placebo and HDB tirofiban groups, respectively (hazard ratio 0.51, 95% confidence interval 0.29 to 0.88; p = 0.01). This difference was mainly due to the reduction of myocardial infarction and bailout use of GP IIb/IIIa inhibitors, with no significant effect on TVR or death. The safety profile did not differ between tirofiban and placebo. CONCLUSIONS: The use of tirofiban, when administered at HDB, is safe and significantly reduces the incidence of ischemic/thrombotic complications during high-risk PCI.
Acute Disease↗
Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and progression to heart failure after acute myocardial infarction.
OBJECTIVES: We used acetylsalicylic acid (ASA) as a probing agent to quantify hydroxyl radical ((*)OH) in Controls and patients with coronary artery disease and to prospectively investigate (*)OH production in patients with myocardial infarction (MI) complicated by heart failure (HF). BACKGROUND: Oxidative stress status (OSS) is a mechanism for transition to HF in experimental heart injury models, but evidence for its causal role in humans is still limited. METHODS: Thirty healthy subjects (Controls), 12 patients with stable angina (Group 1), and 74 patients with ST-segment elevation MI (Group 2) were enrolled. A dose of 250 mg Flectadol was given intravenously before each blood collection to determine the 2,3-dihydroxybenzoic acid/salicylic acid (DHBA/SA) ratio. We also quantified vitamin E and coenzyme Q(10) to monitor antioxidant reserve, as well as tumor necrosis factor (TNF)-alpha, TNF-soluble receptors, interleukin (IL)-6, and IL-1ra to assess inflammatory status. All measurements were repeated at month 6 in Group 2. RESULTS: There were no differences between Controls and Group 1. Group 2 showed increased (*)OH production, peaking at 24 h, whereas vitamin E and coenzyme Q(10) progressively declined. Group 2 patients developing HF during hospitalization (Group 2Bi) presented with an increase of both (*)OH production at discharge and inflammatory status, as compared with patients without HF (Group 2Ai), persisting at month 6 in post-MI patients with HF (Group 2Bii). CONCLUSIONS: We found a distinct pattern of (*)OH generation in post-MI patients who show progression to HF. The interplay between OSS and inflammatory status should be targeted as a possible mechanism of progression to post-MI left ventricular dysfunction.
Aged↗
Transcription reinitiation properties of bacteriophage T7 RNA polymerase.
We have analyzed the kinetics of transcription initiation and reinitiation in vitro by one of the simplest and best characterized transcription machineries, bacteriophage T7 RNA polymerase (T7 RNAP). We used a short transcription unit with T7-specific promoter and terminator elements as a template, and a heparin challenge assay to distinguish the first transcription cycle from the subsequent ones. When present at sub-saturating concentrations with respect to template DNA, T7 RNAP could find its promoter and initiate the first transcription cycle in less than 1min. Reinitiation under the same conditions proceeded more slowly, with only three new transcription cycles being completed in 10min; after that time, reinitiation practically ceased. When the polymerase was in large excess over template DNA, however, reinitiation proceeded linearly for longer times, at a rate of 1cycle/min. Our data suggest that polymerase recycling represents a critical step in T7 RNAP transcription, and that such a step may become rate-limiting for transcription at sub-saturating polymerase concentrations.
DNA↗
Improved recognition of dysfunctioning myocardial segments by longitudinal strain rate versus velocity in patients with myocardial infarction.
Doppler tissue imaging (DTI) can measure myocardial velocities but velocities alone cannot distinguish active from passive wall motion, whereas this is possible by strain rate (SR) imaging (SRI). We evaluated the accuracy of SRI for recognition of abnormal regional systolic function compared with DTI, B-mode echocardiography, and anatomic M-mode in 24 patients with myocardial infarction who underwent gated stress Tc 99m sestamibi scan. Sensitivity and specificity for recognition of infarct segments were 91% and 84% for visual SRI, 63% and 73% for visual DTI, 78% and 71% for B-mode echocardiography, and 87% and 77% for anatomic M-mode, respectively. Peak SRs correlated with wall-motion assessment by B-mode echocardiography better than peak velocities (P =.66 vs.10), with less overlap between groups. Therefore, SRI improves evaluation of regional wall motion compared with DTI and conventional ultrasound techniques in patients with myocardial infarction, mainly because it identifies segments that are moving passively but not shortening normally.
Aged↗
The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart.
AIM: The objective behind the Euro Heart Survey on diabetes and the heart was to study the prevalence of abnormal glucose regulation in adult patients with coronary artery disease (CAD). METHODS AND RESULTS: The survey engaged 110 centres in 25 countries recruiting 4196 patients referred to a cardiologist due to CAD out of whom 2107 were admitted on an acute basis and 2854 had an elective consultation. Patient data were collected via a web-based case record form. An oral glucose tolerance test (OGTT) was used for the characterisation of the glucose metabolism. Thirty-one per cent of the patients had diabetes. An OGTT was performed on the 1920 patients without known diabetes, of whom 923 had acute and 997 had a stable manifestation of CAD, respectively. In patients with acute CAD, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group these proportions were 37% and 14%. CONCLUSION: This survey demonstrates that normal glucose regulation is less common than abnormal glucose regulation in patients with CAD. OGTT easily discloses the glucometabolic state and should be a routine procedure. The knowledge of glucometabolic state among these patients should influence their future management because it has great potential to improve the outcome.
Adult↗
Arginase pathway in human endothelial cells in pathophysiological conditions.
Objective. - Arginase is a nitric oxide synthase-alternative pathway for l-arginine breakdown leading to biosynthesis of urea and l-ornithine. Arginase pathway is inducible by inflammatory molecules-such as cytokines and bacterial endotoxin-in macrophages and smooth muscle cells. The presence of an arginase pathway in human endothelial cells and its possible modulation by inflammation are unknown. Methods. - We have: (i) characterised arginase pathway in terms of activity, isoform type and gene expression in a primary human umbilical vein endothelial cells (HUVEC) line; (ii) evaluated arginase functional role in cell proliferation with the aid of l-norvaline, an arginase inhibitor and (iii) determined the effects of tumour necrosis factor-alpha and endotoxin on arginase pathway. Results. - HUVEC showed a baseline arginase activity and expression of both arginase isoforms (arginase I and II (A-I and A-II, respectively)) which resulted in l-norvaline-inhibitable cellular polyamine synthesis. The baseline arginase activity is important for HUVEC proliferation as cell cycle analysis and nuclear factor Ki-67 immunostaining revealed. Following incubation with inflammatory molecules, arginase activity increased but HUVEC cell cycling decreased. Conclusions. - A-I and A-II are constitutively expressed in HUVEC where they take part to the regulation of cell cycling. Although arginase activity is positively modulated by inflammatory molecules, it is insufficient to counteract the overall cell cycling inhibiting effects of inflammation.
Antibodies, Antinuclear↗
Co-expression and modulation of neuronal and endothelial nitric oxide synthase in human endothelial cells.
Despite originally identified in neurones, the neuronal type of nitric oxide synthase (nNOS) is present also in cardiac and skeletal myocytes. Whether nNOS is functionally expressed in human endothelial cells--as the endothelial enzyme (eNOS)--is unknown. Human umbilical vein endothelial cells (HUVEC) were studied under control culture conditions and after 48 h treatment with cytomix (human tumour necrosis factor-alpha, interferon-gamma and E. coli endotoxin). We tested: (i) localisation and expression of nNOS and eNOS proteins by immunostaining and immunoblotting; (ii) activity of nNOS and eNOS by measuring L-arginine to L-citrulline conversion with 1-(2-trifluoromethylphenyl)imidazole (TRIM), a specific nNOS antagonist, in sub-cellular fractions; (iii) intracellular cGMP levels, as a marker for nitric oxide production, after TRIM pre-treatment, by radioimmunoassay. nNOS protein was expressed in the cytosolic fraction and immunolocalised in cultured HUVEC, and co-localised with the eNOS protein in frozen sections of the human umbilical cord. nNOS protein contributed to total L-citrulline production as TRIM selectively and dose-dependently reduced L-citrulline synthesis in the cytosolic but not particulate fraction of HUVEC. Similarly, TRIM reduced intracellular cGMP content both at baseline and after stimulation with a calcium ionophore. Cytomix down-regulated the expression and function of both nNOS and eNOS while no inducible NOS (iNOS) was detected. In conclusion, a functional neuronal type of NOS is co-expressed with the endothelial NOS type in HUVEC, suggesting a possible role for nNOS in regulation of blood flow.
Calcium↗
Effect of nolomirole on monocrotaline-induced heart failure.
Neurohormonal activation has been shown to be a major factor in congestive heart failure progression and mortality. The beneficial effects obtained in clinical trials with angiotensin converting enzyme (ACE) inhibitors, beta-blockers and aldosterone antagonists have confirmed this hypothesis. 5,6-Diisobutirroyloxy-2-methyl-aminotetraline hydrochloride (nolomirole) is a selective agonist of prejunctional D(2)-dopaminergic and alpha(2)-adrenergic receptors. The stimulation of these receptors inhibits catecholamine release from sympathetic nerve endings. To confirm that this mechanism can be useful in congestive heart failure, we studied the effects of nolomirole on monocrotaline-induced congestive heart failure. The ACE inhibitor trandolapril was used as reference compound. Rats were given single intraperitoneal injection of either saline (control group; n=20) or monocrotaline (50 mg kg(-1)). Three days later, the monocrotaline-treated animals were randomly allocated (n=50 per group) to oral treatment with distilled water (vehicle group), nolomirole (0.25 mg kg(-1)) twice a day, or trandolapril (0.3 mg kg(-1)) once a day up to sacrifice. On the fourth week after monocrotaline injection, animals with signs of congestive heart failure were sacrificed for evaluation of heart hypertrophy and neuroendocrine alterations. Atrial natriuretic peptide (ANP) and alderosterone were determined by radioimmunoassay in plasma. Tissue norepinephrine concentration was quantified by high-pressure liquid chromatography. Nolomirole and trandolapril significantly reduced (a) hypertrophy of right atria and ventricles, (b) plasma levels of ANP and presence of pleural/peritoneal effusions and (c) norepinephrine depletion of right ventricle. These findings confirmed that nolomirole, like trandolapril, is able to attenuate the heart failure signs in the monocrotaline-induced congestive heart failure model.
Administration, Oral↗
Assessment of left ventricular volume and function by integration of simplified 3D echocardiography, tissue harmonic imaging and automated extraction of endocardial borders.
BACKGROUND: Quantitative three-dimensional echocardiography (3DEcho) of left ventricle (LV) is still limited because of the need for manually tracing endocardial borders: this can increase observer variability depending on the quality of fundamental (FUND) 2D images. We tested the combination of a simplified 3DEcho technique for LV reconstruction with automated endocardial border detection (Digital Echo Quantification, DEQ) and tissue harmonic imaging (THI) for enhancement of endocardium-cavity interface. METHODS: Twenty-five consecutive patients with ischaemic heart disease and dilated or distorted LV underwent 3DEcho and gated-SPECT nuclear examinations evaluating: (a) end-diastolic and end-systolic volumes (EDV, ESV); (b) ejection fraction (EF); (c) volume/time curve (VTC). Thereafter, 3DEcho was applied to 47 patients with acute myocardial infarction (AMI) at pre-discharge and 6 months to evaluate remodelling. RESULTS: Integrated 3DEcho values in THI modality were obtained in 84% of patients and correlated well with nuclear data for EDV (r = 0.95, mean difference = -2.2 +/- 15.8 ml), ESV (r = 0.98, mean difference = -3.5 +/- 10.2 ml), and EF (r = 0.82, mean difference = 0.6 +/- 6.4%; all mean differences NS vs. 0), with an interobserver variability of 4.9, 5.7 and 8.2% for EDV, ESV and EF respectively. Automated VTC by 3DEcho in THI modality reproduced well that obtained by nuclear technique (r = 0.96) and allowed recognition of LV remodelling in 36% of patients at 6 months. Integrated 3DEcho values in FUND modality were obtained only in 52% of patients and showed much higher errors and interobserver variability. CONCLUSIONS: THI permits accurate 3D reconstruction of LV borders detected by DEQ, allowing automated VTC throughout the cardiac cycle as well as study of LV remodelling.
Algorithms↗
High-dose bolus tirofiban and sirolimus eluting stent versus abiciximab and bare metal stent in acute myocardial infarction (STRATEGY) study--protocol design and demography of the first 100 patients.
BACKGROUND: Primary bare metal stenting and abciximab infusion are currently considered the best available reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI). Sirolimus eluting stents (SES), compared to bare metal stent (BMS), greatly reduce the incidence of binary restenosis and target vessel revascularisation (TVR), but their use on a routine basis results in a significant increase in medical costs. With current European list prices, the use of tirofiban instead of abciximab would save enough money to absorb the difference between SES and BMS. AIM: To assess whether in patients with STEMI the combination of SES with high dose bolus (HDB) tirofiban results in a similar incidence of major cardiovascular events (MACE) but in a lower binary restenosis rate after six months compared to BMS and abciximab. METHODS AND RESULTS: 160 patients are required to satisfy the primary composite end-point, including MACE and binary restenosis. The study is ongoing: the current paper focuses on the methodology and demography of the first 100 patients so far enrolled. Patients randomised to HDB tirofiban (n = 50, mean age: 62 +/- 12, 40 males) and abciximab (n = 50, mean age: 63 +/- 12, 38 males) do not differ for medical history, presentation profile, medications at discharge, angiographic profile and creatine-kinase MB-fraction at peak. CONCLUSIONS: The results of the trial will be available by the end of 2004: they will be crucial for the cardiologists to know whether the gold standard for AMI treatment should be reconsidered after the introduction of SES into the clinical practice.
Abciximab↗
Improvement of cardiac function and beta-adrenergic signal transduction by propionyl L-carnitine in congestive heart failure due to myocardial infarction.
OBJECTIVES: Earlier studies have revealed beneficial effects of metabolic therapy in animals with congestive heart failure (CHF) due to myocardial infarction. Because heart failure is also associated with attenuated response to catecholamines, we examined the effects of propionyl L-carnitine (PLC) (a carnitine derivative) therapy on the beta-adrenoceptor (beta-AR) signal transduction in the failing heart. METHODS: Heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated with or without 100 mg/kg (intraperitoneally, daily) PLC for 5 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Crude membranes were isolated from the remote, nonischemic (viable) left ventricle and examined for changes in beta-AR and adenylyl cyclase (AC) activity. RESULTS: Animals with heart failure exhibited depressions in ventricular function, positive inotropic response to isoproterenol, beta-AR receptor density and basal AC activity; these changes were also attenuated by PLC treatment. The stimulation of AC activities with isoproterenol, 5'-guanyl imidodiphosphate, forskolin and sodium fluoride was decreased in the failing hearts and these changes were also prevented by PLC treatment. CONCLUSION: The results indicate that metabolic therapy with PLC not only attenuates the defects in heart function but also prevents changes in the beta-AR signal transduction in CHF due to myocardial infarction.
Adenylyl Cyclases↗